WO2023059903A1 - Synthèse de mavorixafor et de ses intermédiaires - Google Patents

Synthèse de mavorixafor et de ses intermédiaires Download PDF

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WO2023059903A1
WO2023059903A1 PCT/US2022/046094 US2022046094W WO2023059903A1 WO 2023059903 A1 WO2023059903 A1 WO 2023059903A1 US 2022046094 W US2022046094 W US 2022046094W WO 2023059903 A1 WO2023059903 A1 WO 2023059903A1
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compound
formula
boc
group
reaction mixture
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PCT/US2022/046094
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English (en)
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Roger Hanselmann
Karel Marie Joseph Brands
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X4 Pharmaceuticals, Inc.
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Priority to AU2022360035A priority Critical patent/AU2022360035A1/en
Priority to CA3233731A priority patent/CA3233731A1/fr
Publication of WO2023059903A1 publication Critical patent/WO2023059903A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/17—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/18—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton containing amino groups bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to methods for synthesizing mavorixafor, and to intermediates thereto.
  • CX-C chemokine receptor type 4 also known as fusin or cluster of differentiation 184 (CD 184)
  • CD 184 is a seven transmembrane G-protein coupled receptor (GPCR) belonging to Class I GPCR or rhodopsin-like GPCR family.
  • GPCR G-protein coupled receptor
  • CXCR4 Under normal physiological conditions, CXCR4 carries out multiple roles and is principally expressed in the hematopoietic and immune systems. CXCR4 was initially discovered as one of the co- receptors involved in human immunodeficiency virus (HIV) cell entry.
  • HIV human immunodeficiency virus
  • CXCL12 previously designated SDF-la, is the only known ligand for CXCR4.
  • CXCR4 mediates migration of stem cells during embryonic development as well as in response to injury and inflammation.
  • Multiple roles have been demonstrated for CXCR4 in human diseases such as cellular proliferative disorders, Alzheimer’s disease, HIV, rheumatoid arthritis, pulmonary fibrosis, and others.
  • expression of CXCR4 and CXCL12 have been noted in several tumor types.
  • CXCL12 is expressed by cancer-associated fibroblast (CAFs) and is often present at high levels in the tumor microenvironment (TME).
  • CAFs cancer-associated fibroblast
  • TEE tumor microenvironment
  • CXCR4/CXCL12 has been associated with a poor prognosis and with an increased risk of metastasis to lymph nodes, lung, liver, and brain, which are sites of CXCL12 expression.
  • CXCR4 is frequently expressed on melanoma cells, particularly the CD133+ population that is considered to represent melanoma stem cells; in vitro experiments and murine models have demonstrated that CXCL12 is chemotactic for such cells.
  • Mavorixafor, and pharmaceutically acceptable compositions thereof are effective as CXC receptor type 4 (CXCR4) inhibitors, and are useful for treating a variety of diseases, disorders, or conditions associated with CXCR4, such as hyperproliferative conditions including various cancers.
  • CXCR4 CXC receptor type 4
  • the methods and intermediates of the present invention are useful for preparing mavorixafor, which is described in, e.g., US patent application serial number 16/215,963 (US 10,548,889), in the name of Brands, the entirety of which is incorporated herein by reference.
  • the present invention relates to certain novel intermediates to the synthesis of mavorixafor that are easier to isolate, purify, and/or handle, and/or are more stable in comparison to corresponding intermediates in the existing methods.
  • the present compounds are generally prepared by assembly of three fragments F-l, F-2, and F-3, according to Scheme I set forth below: Scheme I
  • R 1 is H, a suitable hydroxyl protecting group, or, taken with the oxygen atom to which it is bound, a leaving group
  • R 2 and R 4 independently are H, or a suitable amino protecting group
  • R 3 is H, or a suitable benzimidazole protecting group
  • L is a suitable leaving group
  • M is a metal selected from alkali metals.
  • Fragment F-1 may be prepared using methods known in the art, for example as described in US patent application serial number 16/215,963 (US 10,548,889); US 7,354,934; and Crawford et al., Organic Process Research & Development, 2008, 12, 823-830; the entire contents of each of which are incorporated herein by reference.
  • the present invention provides a compound F-2: wherein:
  • R 1 is H, a suitable hydroxyl protecting group, or, taken with the oxygen atom to which it is bound, a leaving group;
  • R 2 and R 4 independently are H, or a suitable amino protecting group
  • M is a metal selected from alkali metals.
  • Leaving groups are well known in the art and include those described in detail in Leaving group, Gold Book, IUPAC. 2009, ISBN 978-0-9678550-9-7, the entirety of which is incorporated herein by reference.
  • Suitable hydroxyl and amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • R 1 taken with the oxygen atom to which it is bound, is selected from esters, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, tosylate, mesylate, tritiate, or carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloro ethyl, 2-(trimethylsilyl)ethyl, 2- (phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, tri ethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p- halobenzyl, 2, 6-di chlorobenzyl, p-cy anobenzyl, 2- and 4-picolyl.
  • R 1 is H.
  • R 2 taken with the nitrogen atom to which it is bound, is selected from, but is not limited to, aralkylamines, carbamates, allyl amines, amides, and the like, e.g., t- butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, di chloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, pivaloyl and the like.
  • aralkylamines e.g., t- butyloxycarbonyl (Boc), ethyloxycarbon
  • R 2 is Boc.
  • R 4 taken with the nitrogen atom to which it is bound, is selected from, but is not limited to, aralkylamines, carbamates, allyl amines, amides, and the like, e.g., t- butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, di chloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, pivaloyl and the like.
  • R 4 is Boc
  • both R 2 and R 4 are Boc.
  • M is Na.
  • M is K.
  • the present invention provides a compound of the formula F- 2a:
  • R 2 , R 4 and M are as defined herein, both singly and in combination.
  • the present invention provides a compound of the formula F-
  • the present invention provides a compound of the formula F-
  • the present invention provides a compound of the formula F-
  • Compound F-2d can be efficiently synthesized with bisulfite salts and the corresponding aldehyde, compound B-l as depicted in Example 1 below.
  • R 1 , R 2 , R 4 and M are as defined above for compound F-2.
  • the present invention provides methods for preparing compounds of formulae D, C, B, A, and F-2 according to the steps depicted in Scheme II, above.
  • R 1 , R 2 , R 4 and M are as defined above for compound F-2.
  • the amino group of compound E is protected with a suitable protecting group.
  • suitable protecting groups for amino groups are well known to one of ordinary skill in the art and are as defined above for compound F-2.
  • the protecting group is Boc, Cbz, ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, di chloroacetyl, tri chloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, or pivaloyl.
  • the protecting group is Boc.
  • Methods for protecting amino groups are well known to one of ordinary skill in the art and typically include a reaction between a compound bearing an amino group and a suitable reagent of formula PG ⁇ G 1 , wherein PG 1 is a protecting group and LG 1 is a suitable leaving group. Exemplary reactions include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • compound E is protected by reacting it with a reagent selected from Boc-Cl, Cbz-Cl and (Boc)2O.
  • compound E is protected by reacting it with (Boc)2O.
  • the protection is performed in a solvent selected from CH2Q2, THF, DMF and MeCN. In one embodiment, the protection is performed in MeCN. In certain embodiments, the protection is performed by using 1 to 1.5 molar equivalents of (Boc)2O. In one embodiment, the protection is performed by using 1 to 1.2 molar equivalents of (Boc)2O. In one embodiment, the protection is performed by using 1.2 molar equivalents of (Boc)2O. In certain embodiments, the protection is performed in the presence of a catalyst selected from DMAP and pyridine. In one embodiment, the protection is catalyzed by DMAP.
  • the protection is performed without a catalyst. In certain embodiments, the protection is performed at 20 to 60°C. In one embodiment, the protection is performed at 35 to 45°C. In one embodiment, protection is performed at 40°C. In certain embodiments, the protection is performed by stirring the reaction mixture for 0 to 2 hours. In one embodiment, protection is performed by stirring the reaction mixture for 0 to 1 hour. In another embodiment, protection is performed by stirring the reaction mixture for 0 to 30 minutes. In another embodiment, protection is performed by stirring the reaction mixture for 0 minutes. According to one embodiment, the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step 1A in Example 1 below. In yet another embodiment, the compound D is a non-isolated intermediate.
  • the -NH- group of compound D is protected with a suitable protecting group.
  • suitable protecting groups for -NH- groups are well known to one of ordinary skill in the art and are as defined above for compound F-2.
  • the protecting group is Boc, Cbz, ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, di chloroacetyl, tri chloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, or pivaloyl.
  • the protecting group is Boc.
  • Methods for protecting amino groups are well known to one of ordinary skill in the art and typically include a reaction between a compound bearing an amino group and a suitable reagent of formula PG ⁇ G 1 , wherein PG 1 is a protecting group and LG 1 is a suitable leaving group. Exemplary reactions include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • compound D is protected by reacting it with a reagent selected from Boc-Cl, Cbz-Cl and (Boc)2O.
  • compound D is protected by reacting it with (Boc)2O.
  • the protection is performed in a solvent selected from CH2Q2, THF, DMF and MeCN. In one embodiment, the protection is performed in MeCN. In certain embodiments, the protection is performed by using 1 to 1.5 molar equivalents of (Boc)2O. In one embodiment, the protection is performed by using 1 to 1.2 molar equivalents of (Boc)2O. In one embodiment, the protection is performed by using 1.2 molar equivalents of (Boc)2O. In certain embodiments, the protection is performed in the presence of a catalyst selected from DMAP and pyridine. In one embodiment, the protection is catalyzed by DMAP.
  • the protection is performed without a catalyst. In certain embodiments, the protection is performed at 20 to 60°C. In one embodiment, the protection is performed at 35 to 45°C. In one embodiment, protection is performed at 40°C. In certain embodiments, the protection is performed by stirring the reaction mixture for 0 to 2 hours. In one embodiment, protection is performed by stirring the reaction mixture for 0 to 1 hour. In another embodiment, protection is performed by stirring the reaction mixture for 0 to 30 minutes. In another embodiment, protection is performed by stirring the reaction mixture for 0 minutes. According to one embodiment, the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step IB in Example 1 below. In another embodiment, the compound C is a non-isolated intermediate. In yet another embodiment, both steps S-l and S-2 are performed in a single reaction vessel.
  • step S-3 the acetal group of compound C is deprotected.
  • Methods for deprotecting acetal groups are well known to one of ordinary skill in the art and typically include a reaction between a compound bearing an acetal group and a suitable acid. Exemplary reactions include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • compound C is deprotected by reacting it with an acid selected from glacial acetic acid, pTSA, HC1 and H2SO4.
  • compound C is deprotected by reacting it with glacial acetic acid.
  • the deprotection is performed wherein glacial acetic acid is used as solvent. In certain embodiments, the deprotection is performed in presence of NaCl. In certain embodiments, the deprotection id performed at 20 to 60°C. In one embodiment, the deprotection is performed at 25 to45°C. In one embodiment, deprotection is performed at 30°C. In certain embodiments, the deprotection is performed by stirring the reaction mixture for 0 to 5 hours. In one embodiment, deprotection is performed by stirring the reaction mixture for 1 to 4 hours. In another embodiment, deprotection is performed by stirring the reaction mixture for 2 to 3 hours. In another embodiment, deprotection is performed by stirring the reaction mixture for 3 hours.
  • the product after deprotection is treated with decolorizing activated charcoal in heptane at 25 to 55°C for 1 to 3 hours. In an embodiment, the product after deprotection is treated with decolorizing activated charcoal in heptane at 35 to 45°C for 1 to 2 hours. In an embodiment, the product after deprotection is treated with decolorizing activated charcoal in heptane at 40°C for 1 hour.
  • the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step 1C in Example 1 below.
  • the compound B is a non-isolated intermediate.
  • step S-4 the aldehyde group of compound B is converted to a bisulfite adduct.
  • Aldehyde-bisulfite adducts are well known to one of the ordinary skill in the art and include those described in detail in Kissane et al, Tetrahedron Letters, 54 (2013), 6587-6591, the entirety of which is incorporated herein by reference.
  • M is Na or K. In other embodiments, M is Na.
  • Methods for converting aldehyde groups to bisulfite adducts are well known to one of ordinary skill in the art and typically include a reaction between a compound bearing an aldehyde group and metabisulfite salt of an alkali metal.
  • compound B is converted to a bisulfite adduct by reacting it with a compound of formula M2S2O5, wherein M is an alkali metal.
  • compound B is converted to a bisulfite adduct by reacting it with a compound of formula M2S2O5, wherein M is selected from Na and K.
  • compound B is converted to a bisulfite adduct by reacting it with a compound of formula M2S2O5, wherein M is Na.
  • compound B is converted to a bisulfite adduct by reacting it with a compound of formula M2S2O5, wherein M is K.
  • the reaction is performed by reacting compound B in heptane with M2S2O5 in purified water.
  • the reaction is performed at 20 to 60°C.
  • the reaction is performed at 35 to 45°C.
  • reaction is performed at 40°C.
  • the reaction is performed, wherein 0.5 to 0.8 molar equivalents of M2S2O5 are added in 4 to 8 equal portions.
  • the reaction is performed, wherein 0.625 molar equivalents of M2S2O5 are added in 5 equal portions.
  • the reaction is performed by stirring the reaction mixture for 25 to 60 hours. In one embodiment, reaction is performed by stirring the reaction mixture for 30 to 45 hours. In another embodiment, deprotection is performed by stirring the reaction mixture for 36 hours.
  • the product A is precipitated by cooling the reaction mixture to 5 to 35°C over 2 to 6 hours. In an embodiment, the product A is precipitated by cooling the reaction mixture to 15 to 25°C over 3 to 4 hours. In an embodiment, the product A is precipitated by cooling the reaction mixture to 20°C over about 3 hours. In certain embodiments, the precipitated product A is purified by washing it with pre-mixed 1 : 1 mixture of THF and n- heptane at 5 to 35°C.
  • the precipitated product A is purified by washing it with pre-mixed 1 : 1 mixture of THF and n-heptane at 15 to 25°C. In one embodiment, the precipitated product A is purified by washing it with pre-mixed 1 : 1 mixture of THF and n-heptane at 20°C. In certain embodiments, the precipitated product A is purified by washing it with n-heptane at 5 to 35°C, for example, one, two, three, four or five times. In one embodiment, the precipitated product A is purified by washing it with n-heptane at 15 to 25°C, for example, one, two, or three times.
  • the precipitated product A is purified by washing it with n-heptane at 20°C, for example, one, two, or three times. In certain embodiments, the precipitated product A is purified by washing it with MeCN.
  • the solid product A is dried under a flow of nitrogen, for example, warm nitrogen. In some embodiments, product A is dried under nitrogen at 20 to 60°C for an appropriate period of time, such as about 5 to 25 hours. In one embodiment, product A is dried under nitrogen at 35 to 40°C for an appropriate period of time, such as about 10 to 14 hours. In one embodiment, the solid product A is dried under a flow of nitrogen at 38°C, for example, for about 12 hours. In one embodiment, the reaction is performed as described in the Step ID in Example 1 below.
  • Product A may be used as obtained from step S-4, or the hydroxyl group is optionally protected.
  • the hydroxyl group of compound A is protected with a suitable hydroxyl protecting group.
  • Suitable protecting groups for hydroxyl groups are well known to one of ordinary skill in the art and are as defined above for compound F-2.
  • Methods for protecting hydroxylgroups are well known to one of ordinary skill in the art and typically include a reaction between a compound bearing a hydroxyl group and a suitable reagent of formula PG 3 LG 3 , wherein PG 3 is a protecting group and LG 3 is a suitable leaving group.
  • Exemplary reactions include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • the present invention provides methods for preparing compounds of formulae G and F-3 according to the steps depicted in Scheme III, above.
  • R 3 is a suitable benzimidazole protecting group
  • L is a suitable leaving group.
  • Suitable benzimidazole protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • R 3 taken with the nitrogen atom to which it is bound, is selected from, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like, e.g., t- butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, di chloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, pivaloyl and the like.
  • R 3 is Boc.
  • L is a suitable leaving group.
  • Suitable leaving groups are well known in the art, e.g., see, Advanced Organic Chemistry, J. March, 5 th Edition, John Wiley and Sons, 2000. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, and diazonium moieties.
  • L is halogen.
  • L is an optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, or optionally substituted arylsulfonyloxy.
  • L is a halogen.
  • L is chloro.
  • a cyclization reaction is carried out between compound J and a compound of formula H.
  • Acid-catalyzed cyclization reactions between o-arylenediamines and carboxylic acids, or derivatives thereof, are well known to one of ordinary skill in the art, e.g., see, E. C. Wagner and W. H. Millett, Benzimidazole, Organic Syntheses, (1943), Collective Volume 2, page 65.
  • cyclization reaction between compound J and a compound of formula H is catalyzed by an acid selected from formic acid, HC1, HBr, H2SO4 and H3PO4.
  • the cyclization reaction is catalyzed by HC1.
  • the cyclization reaction is performed in a solvent selected from water, DMF and MeCN. In one embodiment, the solvent is water. In certain embodiments, the cyclization reaction is performed by using 1 to 3 molar equivalents of chloroacetic acid. In one embodiment, the cyclization reaction is performed by using 1 to 1.7 molar equivalents of chloroacetic acid. In one embodiment, the cyclization reaction is performed by using about 1.5 molar equivalents of chloroacetic acid. In certain embodiments, the cyclization reaction is performed at about 40 to 120°C. In one embodiment, the cyclization reaction is performed at about 70 to 90°C. In one embodiment, cyclization reaction is performed at about 80°C.
  • the cyclization reaction is performed by allowing compound J and compound H to contact each other for about 5 to 35 hours. In one embodiment, cyclization reaction is performed by allowing compound J and compound H to contact each other for about 15 to 25 hours. In another embodiment, the cyclization reaction is performed by allowing compound J and compound H to contact each other for about 20 hours.
  • the product G is precipitated by cooling the reaction mixture to about 0 to 25°C over about 0 to 4 hours and adding potassium phosphate solution to adjust the pH of the reaction mixture to 5 to 9. In one embodiment, the product G is precipitated by cooling the reaction mixture to about 5 to 15°C over about 1 to 2 hours and adding potassium phosphate solution to adjust the pH of the reaction mixture to 6.8 to 7.2.
  • the product G is precipitated by cooling the reaction mixture to 10°C for about 1 hour and adding potassium phosphate solution to adjust the pH of the reaction mixture to about 7.
  • the precipitated product G is purified by washing it with water. The washing is optionally performed at a reduced temperature, for example, at 0 to 25°C. The washing is optionally repeated, for example, 1 to 7 times.
  • the precipitated product G is purified by washing it with water at about 5 to 15°C a total of 2 to 5 times.
  • the precipitated product G is purified by washing it with water at about 10°C a total of 3 times.
  • the precipitated product G is purified by washing it with MeCN at 0 to 30°C, 2 to 10 times. In one embodiment, the precipitated product G is purified by washing it with MeCN at 5 to 15°C, 5 to 8 times. In one embodiment, the precipitated product G is purified by washing it with MeCN at about 10°C, for a total of 6 times.
  • the solid product G is dried under a flow of nitrogen, which is optionally performed at a reduced temperature, for example, at 5 to 35°C. In one embodiment, the solid product G is dried under a flow of nitrogen at 15 to 25°C. In some embodiments, the product G is dried until its water content is ⁇ 25% w/w by Karl-Fisher analysis.
  • the product G is dried until its water content is ⁇ 15% w/w by Karl- Fisher analysis. In one embodiment, the solid product G is dried under a flow of nitrogen at about 20°C, for example, until its water content is ⁇ 15% w/w by Karl-Fisher analysis. In certain embodiments, the solid product G is dried under a flow of nitrogen at about 10 to 50°C, for example, until its water content is ⁇ 5% w/w by Karl-Fisher analysis. In one embodiment, the solid product G is dried under a flow of nitrogen at about 25 to 35°C, for example, until its water content is ⁇ 5% w/w by Karl-Fisher analysis.
  • the solid product G is dried under a flow of nitrogen at about 30°C, until its water content is ⁇ 5% w/w by Karl-Fisher analysis. In certain embodiments, the solid product G is dried under a flow of nitrogen at about 30 to 70°C, until its water content is ⁇ 1% w/w by Karl-Fisher analysis. In one embodiment, the solid product G is dried under a flow of nitrogen at about 45 to 55°C, until its water content is ⁇ 1% w/w by Karl-Fisher analysis. In one embodiment, the solid product G is dried under a flow of nitrogen at about 50°C, until water content is ⁇ 1% w/w by Karl-Fisher analysis. In one embodiment, the reaction is performed as described in the Step 2A in Example 2 below.
  • step S-7 the -NH- group of compound G is protected with a suitable benzimidazole protecting group.
  • Suitable benzimidazole protecting groups are well known to one of ordinary skill in the art and are as defined above for compound F-3.
  • Methods for protecting the -NH- group of benzimidazoles are well known to one of ordinary skill in the art and typically include a reaction between a compound bearing a benzimidazole moiety with an -NH- group and a suitable reagent of formula PG 4 LG 4 , wherein PG 4 is a protecting group and LG 4 is a suitable leaving group.
  • Exemplary reactions include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
  • compound G is protected by reacting it with a reagent selected from Boc-Cl, Cbz-Cl and (Boc)2O. In one embodiment, compound G is protected by reacting it with (Boc)2O. In certain embodiments, the protection is performed in a solvent selected from CH2CI2, THF, DMF, and MeCN. In one embodiment, the protection is performed in DMF. In certain embodiments, the protection is performed by using 1 to 2 molar equivalents of (Boc)2O. In one embodiment, the protection is performed by using 1 to 1.6 molar equivalents of (Boc)2O.
  • the protection is performed by using 1.4 molar equivalents of (Boc)2O. In certain embodiments, the protection is performed in the presence of a catalyst selected from DMAP and pyridine. In one embodiment, the protection is catalyzed by DMAP. In yet another embodiment, the protection is performed without a catalyst. In certain embodiments, the protection is performed in the presence of a base selected from DIPEA and TEA. In one embodiment, the protection is performed in the presence of DIPEA. In certain embodiments, the protection is performed at about 20 to 60°C. In one embodiment, the protection is performed at about 35 to 45°C. In one embodiment, protection is performed at about 40°C.
  • the protection is performed by stirring the reaction mixture for about 5 to 30 hours or until complete. In one embodiment, protection is performed by stirring the reaction mixture for about 10 to 20 hours. In another embodiment, protection is performed by stirring the reaction mixture for about 16 hours. In certain embodiments, after protection the reaction mixture is treated with decolorizing activated charcoal at about 20 to 60°C for at least 40 minutes. In one embodiment, after protection the reaction mixture is treated with decolorizing activated charcoal at about 35 to 45°C for at least 60 minutes. In an embodiment, after protection the reaction mixture is treated with decolorizing activated charcoal at about 40°C for about 60 to 90 minutes.
  • the product F-3 is purified by direct crystallization from the reaction mixture by addition of water at about 20 to 60°C followed by cooling the reaction mixture to effect crystallization. In one embodiment, the product F-3 is purified by direct crystallization from the reaction mixture by addition of water at about 35 to 45°C followed by cooling the reaction mixture to effect crystallization. In some embodiments, the reaction mixture is cooled to about 34 to 36°C over about 30 to 120 minutes. In certain embodiments, the product F-3 is purified by direct crystallization from the reaction mixture by addition of water at about 25 to 60°C followed by cooling the reaction mixture to about 10 to 45°C over about 40 to 80 minutes.
  • the product F-3 is purified by direct crystallization from the reaction mixture by addition of water at about 40°C followed by cooling the reaction mixture to about 35°C over about 60 minutes.
  • crystallization of product F-3 is facilitated by addition of F-3 as seed material.
  • the seed material is added at about 25 to 45°C, followed by cooling the reaction mixture to about 20 to 45°C over about 5 to 75 minutes.
  • the seed material is added at about 34 to 36°C, followed by cooling the reaction mixture to about 28 to 32°C over about 20 to 60 minutes.
  • crystallization of product F-3 is facilitated by addition of F-3 as seed material at about 35°C, followed by cooling the reaction mixture to about 30°C over about 40 minutes.
  • addition of F-3 as seed material is repeated, followed by stirring the reaction mixture at about 20 to 40°C for about 0 to 3 hours. In some embodiments, addition of F-3 as seed material is repeated, followed by stirring the reaction mixture at about 28 to 32°C for about 1 to 2 hours. In one embodiment, addition of F-3 as seed material is repeated, followed by stirring the reaction mixture at about 30°C for about 1.5 hours. In some embodiments, crystallization is initiated by further cooling the reaction mixture to about 5 to 35°C over about 1 to 6 hours. In some embodiments, crystallization is initiated by further cooling the reaction mixture to about 15 to 25°C over about 3 to 4 hours. In one embodiment, crystallization is initiated by further cooling the reaction mixture to about 20°C over about 3 hours.
  • crystallization is initiated by further addition of water at about 5 to 35°C, followed by stirring the reaction mixture for at least 1 hours. In some embodiments, crystallization is initiated by further addition of water at about 15 to 25°C, followed by stirring the reaction mixture for at least 3 hours. In one embodiment, crystallization is initiated by further addition of water at about 20°C followed by stirring the reaction mixture for about 3 hours. In some embodiments, crystallization is initiated by cooling the reaction mixture to about -5 to 15°C over a period of about 1 to 4 hours, followed by stirring at -5 to 15°C for at least 1 hours.
  • crystallization is initiated by cooling the reaction mixture to about 0 to 5°C over a period of about 2.5 hours, followed by stirring at 0 to 5°C for at least 2.5 hours. In one embodiment, crystallization is initiated by cooling the reaction mixture to about 2°C over about 2.5 hours, followed by stirring at about 2°C for about 2.5 hours. In certain embodiments, the crystallized product F-3 is purified by washing it with pre-mixed DMF and water as an about 1 : 1 to 1 :3 mixture, optionally at a reduced temperature of about -5 to 15°C.
  • the crystallized product F-3 is purified by washing it with pre-mixed DMF and water as an about 1 :2 mixture, optionally at a reduced temperature of about 0 to 5°C. In one embodiment, the crystallized product F-3 is purified by washing it with pre-mixed DMF and water as an about 1 :2 mixture, optionally at a reduced temperature of about 2°C. In certain embodiments, the crystallized product F-3 is purified by washing it with purified water at about 0 to 10°C. In some embodiments, the crystallized product F-3 is purified by washing it with purified water at about 0 to 5°C. In one embodiment, the crystallized product F-3 is purified by washing it with purified water at about 2°C.
  • the crystallized product F-3 is dried under vacuum at ⁇ 50°C, for example, until water content is ⁇ 0.2% w/w by Karl-Fisher analysis and DMF content is ⁇ 0.4% w/w. In some embodiments, the crystallized product F-3 is dried under vacuum at ⁇ 30°C, for example, until water content is ⁇ 0.2% w/w by Karl-Fisher analysis and DMF content is ⁇ 0.4% w/w. In one embodiment, the crystallized product F-3 is dried under vacuum at 28°C, until water content is ⁇ 0.2% w/w by Karl-Fisher analysis and DMF content is ⁇ 0.4% w/w. According to one embodiment, the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step 2B in Example 2 below.
  • the present invention provides methods for preparing compounds of formulae Q, P, O, N, M, K and mavorixafor according to the steps depicted in Scheme IV.
  • R 2 and R 4 are as defined above for compounds of formula F-2;
  • R 3 and L are as defined above for compounds of formula F-3;
  • A is selected from an acid such as TFA, HC1, HBr, H 2 SO 4 , H 3 PO 4 and the like; and
  • n is 1, 2 or 3.
  • the compound O is a compound of the formula 0-1:
  • the present invention provides a compound of the formula K-l:
  • Compound K-l can be synthesized by simultaneous deprotection of three Boc groups of compound 0-1, by reacting 0-1 with sulfuric acid, as depicted in Example 3 below. Attempts to crystallize mavorixafor with several other counter-ions have not been successful, or have resulted in products that were highly hygroscopic. Compound K-l is a stable solid, that is easy to isolate, purify and store. Using K-l gives better yields in the subsequent synthetic step compared to using other salt forms. At step S-8, a condensation reaction is carried out between the amino group of compound F-l and the bisulfite adduct of the aldehyde group of a compound of formula F-2a to prepare an imine of formula Q.
  • compound F-l is an acid addition salt thereof, such as the hydrochloride.
  • R 2 is Boc.
  • R 4 is Boc.
  • R 2 and R 4 are both Boc. Imine formation via condensation between an amine and a bisulfite adduct of an aldehyde is well known to one of ordinary skill in the art; see, e.g., Expedient reductive amination of aldehyde bisulfite adducts, Neelakandha S. Mani et al, Synthesis, 2009, volume 23, page 4032, which is hereby incorporated by reference in its entirety. According to certain embodiments, compound F-l is reacted with compound F-2a under appropriate condition.
  • F- 1 is reacted with F-2a in a mixture of THF and ⁇ -heptane in the presence of an aqueous phosphate solution, such as aqueous potassium phosphate.
  • the reaction is carried out at a reduced temperature, such as about -15 to 15°C.
  • the reaction is carried out at a reduced temperature, such as about -5 to 5°C.
  • compound F-l is reacted with compound F-2a in a mixture of THF and ⁇ -heptane in presence of aqueous potassium phosphate at 0°C.
  • compound F-2a is added to the reaction mixture in 1 to 10 portions spaced by 1 to 60 minutes.
  • compound F-2a is added to the reaction mixture in 2 to 6 portions spaced by >10 minutes. In one embodiment, compound F-2a is added to the reaction mixture in four portions spaced by 10 minutes. According to certain embodiments, the reaction mixture is stirred for 0 to 10 hours. According to some embodiments, the reaction mixture is stirred for >1 hour. In one embodiment, the reaction mixture is stirred for 1.5 hours. According to one embodiment, the organic phase of the reaction mixture is directly used for step S-9. According to another embodiment, the compound Q is a non-isolated intermediate. In one embodiment, the reaction is performed as described in the Step 3A in Example 3 below.
  • step S-9 the imine moiety of a compound of formula Q is reduced to prepare an amine of the formula P.
  • R 2 is Boc.
  • R 4 is Boc.
  • R 2 and R 4 are both Boc.
  • Methods of reducing imines to prepare amines are well known to one of ordinary skill in the art; see, e.g., Expedient reductive amination of aldehyde bisulfite adducts, Neelakandha S. Mani et al, Synthesis, 2009, volume 23, page 4032-4036.
  • imine Q is reacted with an appropriate reducing agent such as sodium borohydride in an appropriate solvent, such as a water- THF mixture.
  • the reaction is optionally performed at a reduced temperature such as about -25 to 20°C.
  • imine Q is reacted with sodium borohydride in a water- THF mixture at -10 to 0°C.
  • imine Q is reacted with sodium borohydride in a water- THF mixture at -5°C.
  • imine Q is reacted with sodium borohydride in the presence of zinc chloride.
  • the reaction mixture is stirred for 0 to 5 hours.
  • the reaction mixture is stirred for >1 hour.
  • the reaction mixture is stirred for 1.5 hours.
  • amine P is isolated as an HC1 salt by precipitation.
  • the isolation is performed by cooling a mixture of HC1 salt of compound P and tertbutyl methyl ether, for example to about -25 to 20°C.
  • amine P is isolated as an HC1 salt by precipitation by cooling a mixture of HC1 salt of compound P and tert-butyl methyl ether to about -10 to 0°C.
  • amine P is isolated as an HC1 salt by precipitation by cooling a mixture of HC1 salt of compound P and tert-butyl methyl ether to -5°C.
  • an HC1 salt of compound P is dried under a flow of nitrogen at 10 to 50°C.
  • an HC1 salt of compound P is dried under a flow of nitrogen at >25°C. In one embodiment, HC1 salt of compound P is dried under a flow of nitrogen at 23 °C. According to one embodiment the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step 3B in Example 3 below.
  • a compound of formula P is reacted with a compound of formula F-3, to prepare a compound of formula O.
  • R 3 is Boc.
  • R 2 is Boc.
  • R 4 is Boc.
  • R 2 and R 4 are both Boc.
  • L is chloro.
  • R 2 and R 3 are both Boc.
  • R 2 , R 3 and R 4 are Boc.
  • a compound of formula P is reacted with a compound of formula F-3, in the presence of potassium phosphate.
  • a compound of formula P is reacted with a compound of formula F-3, in a mixture of toluene and purified water.
  • a compound of formula P is reacted with a compound of formula F-3, in the presence of an iodide source such as sodium iodide, potassium iodide, or tetrabutylammonium iodide.
  • an iodide source such as sodium iodide, potassium iodide, or tetrabutylammonium iodide.
  • the reaction is performed at an elevated temperature, such as about 20 to 75°C. In some embodiments, the reaction is performed at an elevated temperature, such as about 35 to 45°C. In one embodiment, the reaction is performed at 40°C.
  • the reaction is performed by stirring the reaction mixture for 5 to 70 hours. In some embodiments, the reaction is performed by stirring the reaction mixture for >30 hours. In one embodiment, the reaction is performed by stirring the reaction mixture for about 30 hours.
  • the reaction mixture is treated with 2-mercaptoacetic acid at 15 to 90°C. In some embodiments, the reaction mixture is treated with 2-mercaptoacetic acid at 45 to 55°C. In one embodiment, the reaction mixture is treated with 2-mercaptoacetic acid at 50°C.
  • the organic phase of the reaction mixture is directly used for step S-ll. According to a certain embodiment, compound O is a non-isolated intermediate. According to one embodiment, the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step 3C in Example 3 below.
  • a compound of formula O is deprotected to remove protecting group R 3 to prepare a compound of formula N.
  • Deprotection methods of benzimidazole protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • a compound of formula N is deprotected to remove protecting group R 2 to prepare compound M.
  • Deprotection methods of amine protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • step S-13 compound M is deprotected to remove protecting group R 4 to prepare compound K.
  • Deprotection methods of amine protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • compound O is the compound of formula 0-1; and the three Boc groups are removed in a single step to prepare a compound of formula K.
  • the three Boc groups of compound 0-1 are removed in a single step to by reacting compound O- 1 with H2SO4 to prepare a compound of formula K-l.
  • Deprotection methods for removing multiple Boc groups in a single step are well known in the art and typically include reacting a compound bearing two or more Boc groups with an acid selected from TFA, HC1, HBr, H2SO4, and H3PO4. Exemplary methods include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
  • compound 0-1 is reacted with H2SO4 in n-butanol at 20 to 90°C. In some embodiments, compound 0-1 is reacted with H2SO4 in n- butanol at 50 to 60°C. In one embodiment, compound 0-1 is reacted with H2SO4 in n-butanol at 55 °C. In one embodiment, organic phase from Step S-10 containing compound 0-1 is directly reacted with H2SO4 in n-butanol.
  • compound 0-1 is reacted with H2SO4 in n-butanol by stirring the reaction mixture for 0 to 10 hours. In some embodiments, compound 0-1 is reacted with H2SO4 in n-butanol by stirring the reaction mixture for >1 hour. In one embodiment, compound 0-1 is reacted with H2SO4 in n-butanol by stirring the reaction mixture for 1.5 hours. In certain embodiments, compound 0-1 is reacted with H2SO4 in n-butanol by stirring the reaction mixture for additional 0 to 10 hours. In some embodiments, compound 0-1 is reacted with H2SO4 in n-butanol by stirring the reaction mixture for additional 4 to 5 hours.
  • compound 0-1 is reacted with H2SO4 in n-butanol by stirring the reaction mixture for additional 4.5 hours.
  • product K-l is precipitated directly from the reaction mixture by cooling the reaction mixture, for example, by cooling to about 0 to 40°C over 1 to 30 hours.
  • product K-l is precipitated directly from the reaction mixture by cooling the reaction mixture, for example, by cooling to about 15 to 25°C over >10 hours.
  • product K-l is precipitated directly from the reaction mixture by cooling the reaction mixture, for example, to about 20°C over about 10 hours.
  • product K-l is isolated by filtration under nitrogen at a reduced temperature, for example at about 5 to 45°C.
  • product K-l is isolated by filtration under nitrogen at a reduced temperature, for example at about 15 to 25°C. In one embodiment, product K-l is isolated by filtration under nitrogen at about 20°C. In certain embodiments, precipitated product K-l is washed with an appropriate non-polar solvent or mixture of non-polar solvents, such as benzene, toluene, xylenes, hexanes, pentane, heptane, n-hexanol, n-heptanol, and/or n-butanol.
  • an appropriate non-polar solvent or mixture of non-polar solvents such as benzene, toluene, xylenes, hexanes, pentane, heptane, n-hexanol, n-heptanol, and/or n-butanol.
  • the mixture of non-polar solvents is a mixture of about 1 : 10 to 10: 1 volume/volume mixture of toluene and n-butanol. In some embodiments, the mixture of non-polar solvents is a mixture of about 4: 1 volume/volume mixture of toluene and n-butanol. In some embodiments, precipitated product K-l is washed with premixed 4: 1 volume/volume mixture of toluene and n- butanol at about 5 to 50°C. In one embodiment, precipitated product K-l is washed with premixed 4: 1 volume/volume mixture of toluene and n-butanol at about 20°C.
  • precipitated product K-l is washed with toluene at about 5 to 55°C. In some embodiments, precipitated product K-l is washed with toluene at about 15 to 25°C. In one embodiment, precipitated product K-l is washed with toluene at about 20°C. In certain embodiments, after the washing step, product K-l is dried under vacuum at 5 to 75°C. In some embodiments, after the washing step, product K-l is dried under vacuum at ⁇ 35°C. In one embodiment, after the washing step, product K-l is dried under vacuum at about 30°C. In one embodiment, the reaction is performed as described in the Step 3D in Example 3 below.
  • a compound of formula K is converted to mavorixafor by reacting compound K with a base.
  • Methods of converting acid salts of amines to corresponding free amines are well known in the art and typically include reacting an acid salt of an amine with a suitable base.
  • compound K is reacted with a base selected from LiOH, NaOH, KOH, Ca(OH) 2 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , CaCO 3 , LiHCO 3 , NaHCO 3 , KHCO 3 , or Ca(HCO 3 ) 2 .
  • compound K is reacted with NaOH.
  • compound K is reacted with aqueous NaOH.
  • compound K-l is reacted with aqueous NaOH in a biphasic solvent mixture of water, toluene and n-butanol.
  • the aqueous NaOH solution is about 1 to 7 M.
  • the aqueous NaOH solution is 3.0 M.
  • nitrogen-purged 0.1 to 2 M sulfuric acid is added to the resulting biphasic reaction mixture to adjust the pH of the aqueous layer to about 7 to 12, if the aqueous layer is not already at the pH of about 7 to 12.
  • reaction of compound K with the base such as NaOH
  • nitrogen-purged 0.3 M sulfuric acid is added to the resulting biphasic reaction mixture to adjust the pH of the aqueous layer to about 9.8 to 10.5, if the aqueous layer is not already at the pH of about 9.8 to 10.5.
  • the pH of the aqueous layer of the resulting biphasic reaction mixture is adjusted to about 8 to 12, if the aqueous layer is not already at the pH of about 8 to 12.
  • the pH of the aqueous layer of the resulting biphasic reaction mixture is adjusted to about 10.0, if the aqueous layer is not already at the pH of about 10.
  • the reaction of compound K with the suitable base after adjusting the pH of the aqueous layer to about 9.8 to 10.5, is performed at about 5 to 55°C.
  • the reaction of compound K with the suitable base after adjusting the pH of the aqueous layer to about 9.8 to 10.5, is performed at about 25 to 35°C. According to one embodiment, the reaction is performed at about 30°C.
  • the reaction mixture is stirred for about 5 to 100 minutes. In some embodiments, the reaction mixture is stirred for about 30 to 60 minutes. In one embodiment, the reaction mixture is stirred for 45 minutes.
  • the organic layer is of the reaction mixture is separated and n-butanol is removed by azeotrope by added toluene and vacuum distillation at 5 to 65°C. In some embodiments, the vacuum distillation is done at 35 to 45°C. According to one embodiment, the vacuum distillation is done at 40°C. According to another embodiment, azeotrope by added toluene is repeated 1 to 5 additional times.
  • azeotrope by added toluene is repeated one additional time.
  • the product, mavorixafor is precipitated by concentrating the reaction mixture by vacuum distillation at about 5 to 65°C.
  • mavorixafor is precipitated by concentrating the reaction mixture by vacuum distillation at about 35 to 45°C.
  • mavorixafor is precipitated by concentrating the reaction mixture by vacuum distillation at about 30°C.
  • the precipitated mavorixafor is redissolved by heating the reaction mixture to about 30 to 90 °C. This temperature is referred to as dissolution temperature.
  • the dissolution temperature is about 60 to 66°C.
  • the dissolution temperature is about 63°C.
  • the temperature of the solution of mavorixafor is adjusted to 0.5 to 5°C ⁇ 0.5°C below the dissolution temperature.
  • the temperature of the solution of mavorixafor is adjusted to 2.5°C ⁇ 0.5°C below the dissolution temperature. This temperature is referred to as seed temperature.
  • the reaction mixture is seeded by addition of a slurry of mavorixafor in toluene at the seed temperature ⁇ 10°C. In some embodiments, the reaction mixture is seeded by addition of a slurry of mavorixafor in toluene at the seed temperature ⁇ 2°C. In certain embodiments, the reaction mixture is stirred at seed temperature ⁇ 5°C for 0.5 to 5 hours. In some embodiments, the reaction mixture is stirred at seed temperature ⁇ 2°C for >1 hour. In one embodiment, the reaction mixture is stirred at seed temperature ⁇ 2°C for 1 hour. In certain embodiments, the reaction mixture is cooled to about 20 to 60°C over about 0.5 to 10 hours.
  • the reaction mixture is cooled to about 38 to 42°C over about 2.5 hours, or >2.5 hours. According to one embodiment, the reaction mixture is cooled to about 40°C over about 2.5 hours. In certain embodiments, the reaction mixture is stirred at about 38 to 42°C for about 1 hour, or >1 hour. According to one embodiment, the reaction mixture is stirred at about 40°C for about 1 hour. In certain embodiments, the reaction mixture is further cooled to about 10 to 50°C over about 0.5 to 10 hours. In some embodiments, the reaction mixture is further cooled to about 28 to 32°C over about 2 hours, or >2 hours. According to one embodiment, the reaction mixture is further cooled to about 30°C over about 2 hours.
  • the reaction mixture is stirred at about 10 to 50°C for about 0 to 10 hours. In some embodiments, the reaction mixture is stirred at about 28 to 32°C for about 1 hour, or >1 hour. According to one embodiment, the reaction mixture is stirred at about 30°C for about 1 hour. In certain embodiments, the reaction mixture is further cooled to about 10 to 40°C over 10 to 100 minutes. In some embodiments, the reaction mixture is further cooled to about 23 to 27°C over 50 minutes, or >50 minutes. According to one embodiment, the reaction mixture is cooled to about 25°C over about 50 minutes. In certain embodiments, the reaction mixture is stirred at about 10 to 50°C for about 0.5 to 10 hours.
  • the reaction mixture is stirred at about 23 to 27°C for about 2 hours, or >2 hours. According to one embodiment, the reaction mixture is stirred at about 25°C for about 2 hours. In certain embodiments, the reaction mixture is further cooled to about -10 to 15°C over about 0.5 to 10 hours. In some embodiments, the reaction mixture is further cooled to about 0 to 5°C over about 4 hours, or >4 hours. According to one embodiment, the reaction mixture is cooled to about 2°C over about 4 hours. In certain embodiments, the reaction mixture is stirred at -5 to 25°C for 5 to 25 hours. In some embodiments, the reaction mixture is stirred at 0 to 5°C for >8 hours.
  • the reaction mixture is stirred at about 2°C for about 12 hours.
  • product mavorixafor is isolated by filtration at about -10 to 25°C.
  • product mavorixafor is isolated by filtration at about 0 to 5°C.
  • product mavorixafor is isolated by filtration at about 2°C.
  • solid product mavorixafor is washed with nitrogen purged toluene about -5 to 25°C.
  • solid product mavorixafor is washed with nitrogen purged toluene about 0 to 5°C.
  • solid product mavorixafor is washed with nitrogen purged toluene at about 2°C.
  • product mavorixafor is dried under vacuum and a flow of nitrogen for about 0.5 to 10 hours. In some embodiments, product mavorixafor is dried under vacuum and a flow of nitrogen for about 1 hour, or >1 hour. In one embodiment, product mavorixafor is dried under vacuum and a flow of nitrogen for about 1.5 hours. In certain embodiments, product mavorixafor is dried under vacuum and a flow of nitrogen at about 10 to 75°C. In some embodiments, product mavorixafor is dried under vacuum and a flow of nitrogen at ⁇ 45°C. In one embodiment, product mavorixafor is dried under vacuum and a flow of nitrogen at about 40°C. According to one embodiment the reaction is performed as described in US patent application serial number 16/215,963 (US 10,548,889). In one embodiment, the reaction is performed as described in the Step 3E in Example 3 below.
  • the present invention provides a method for preparing mavorixafor: comprising the steps of:
  • R 2 and R 4 independently are a suitable amino protecting group
  • M is a metal selected from alkali metals
  • R 3 is a suitable benzimidazole protecting group
  • A is an acid; and n is 1, 2 or 3;
  • the R 2 group of formulae B, F-2a, Q, P, O and N is Boc.
  • R 4 group of formulae B, F-2a, Q, P, O, N and M is Boc.
  • R 2 and R 4 groups of formulae B, F-2a, Q, P, O, N and M are Boc.
  • M of formulae F-2a is sodium or potassium.
  • R 3 group of formulae F-3 and O is Boc.
  • L group of formula F-3 is chloro.
  • each occurrence of R 2 , R 3 and R 4 is Boc.
  • a in formula K is TFA, HC1, HBr, H3PO4 or H2SO4; and n is 1, 2 or 3. According to one embodiment, A in formula K is H2SO4; and n is 3.
  • the compound of formula Q is a non-isolated intermediate.
  • the compound of formula O is a non-isolated intermediate.
  • the sulfonation at step (b) is achieved by reacting the compound of formula B with MS2O5, wherein M is an alkali metal. According to one embodiment, the alkali metal is sodium or potassium.
  • the condensation of the compound of formula F-2a and the compound of formula F-l at step (c) is catalyzed by a suitable condensation catalyst.
  • the suitable condensation catalyst is K3PO4.
  • the reduction at step (d) is achieved by reacting the compound of formula Q with a reducing agent selected from the group comprising NaBHj, NaCNBHs and BH3.
  • the reducing agent is NaBHj.
  • the reaction at step (e) is achieved by reacting the compo aund of formula P with a compound of formula F-3a: N Cl
  • R 2 , R 3 and R 4 are Boc; the deprotection at steps (f), (g) and (h) is achieved simultaneously to generate the compound of formula K, by reacting the compound of formula O with an acid selected from TFA, HC1, HBr, H3PO4, and H2SO4.
  • the acid is H2SO4.
  • a in the formula K is H2SO4; and n is 3.
  • the reaction at step (i) is achieved by reacting the compound of formula K with a suitable base.
  • the suitable base is NaOH.
  • the present invention provides a method for preparing a compound of formula K: wherein:
  • A is an acid; and n is 1, 2 or 3; comprising the steps of:
  • R 2 and R 4 independently are each independently a suitable amino protecting group
  • M is a metal selected from alkali metals
  • R 3 is a suitable benzimidazole protecting group
  • R 2 group of formulae B, F-2a, Q, P, O and N is Boc.
  • R 4 group of formulae B, F-2a, Q, P, O, N and M is Boc.
  • R 2 and R 4 groups of formulae B, F-2a, Q, P, O, N and M are Boc.
  • M of formulae F-2a is sodium or potassium.
  • R 3 group of formulae F-3 and O is Boc.
  • L group of formula F-3 is chloro.
  • each occurrence of R 2 and R 3 is Boc.
  • a in formula K is TFA, HC1, HBr, H3PO4 or H2SO4; and n is 1, 2, or 3. In certain embodiments, A in formula K is H2SO4; and n is 3.
  • the compound of formula Q is a non-isolated intermediate.
  • the compound of formula O is a non-isolated intermediate.
  • the sulfonation at step (b) is achieved by reacting the compound of formula B with MS2O5, wherein M is an alkali metal. According to one embodiment, the alkali metal is sodium or potassium.
  • the condensation of the compound of formula F-2a and the compound of formula F-l at step (c) is catalyzed by a suitable condensation catalyst.
  • the suitable condensation catalyst is K3PO4.
  • the reduction at step (d) is achieved by reacting the compound of formula Q with a reducing agent selected from the NaBIHU, NaCNBHs, and BH3.
  • the reducing agent is NaBIHU.
  • the reaction at step (e) is achieved by reacting the compound of formula P with a compound of formula F-3a:
  • R 2 , R 3 and R 4 are Boc; the deprotection at steps (f), (g) and (h) is achieved simultaneously to generate the compound of formula K, by reacting the compound of formula O with an acid selected from TFA, HC1, HBr, H3PO4, and H2SO4.
  • the acid is H2SO4.
  • a in the formula K is H2SO4; and n is 3.
  • the present invention provides a method for preparing a compound of formula P: wherein:
  • R 2 and R 4 independently are a suitable amino protecting group; comprising the steps of:
  • M is a metal selected from alkali metals
  • R 2 in formulae B, F-2a, Q and P is Boc.
  • R 4 group of formulae B, F-2a, Q and P is Boc.
  • R 2 and R 4 groups of formulae B, F-2a, Q and P are Boc.
  • M in formula F-2a is sodium or potassium.
  • the compound of formula Q is a non-isolated intermediate.
  • the sulfonation at step (b) is achieved by reacting the compound of formula B with MS2O5, wherein M is an alkali metal. According to one embodiment, the alkali metal is sodium or potassium.
  • the condensation of the compound of formula F-2a and the compound of formula F-l at step (c) is catalyzed by a suitable condensation catalyst.
  • the suitable condensation catalyst is K3PO4.
  • the reduction at step (d) is achieved by reacting the compound of formula Q with a reducing agent selected fromNaBIHU, NaCNBHs, and BH3.
  • the reducing agent is NaBIHU.
  • the present invention provides a method for preparing a compound of formula F-2a:
  • R 2 and R 4 independently are a suitable amino protecting group; and M is a metal selected from alkali metals; comprising the steps of:
  • R 2 in formula B and F-2a is Boc.
  • R 4 group of formula B is Boc.
  • R 2 and R 4 groups of formula B are Boc.
  • M in formula F-2a is sodium or potassium.
  • the present invention provides a compound of formula F-2: wherein:
  • R 1 is hydrogen, -C(O)R’, -C(O)OR’, -C(O)NR’R”, -S(O) m R’, -Si(R’) 3 or an optionally substituted group selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, Ci-Ce alkoxy-Ci-Ce alkyl, phenyl, aryl, or heteroaryl;
  • R 2 and R 4 are independently are hydrogen, -C(O)R’, -C(O)OR’, -C(O)NR’R”, - S(O) m R’, -Si(R’)3 or an optionally substituted group selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, Ci-Ce alkoxy-Ci-Ce alkyl, phenyl, aryl, or heteroaryl;
  • R’ and R” independently are hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
  • M is a metal selected from alkali metals.
  • R 1 is hydrogen. In certain embodiments, M is sodium or potassium. In certain embodiments, R 2 is hydrogen, Boc or Cbz. In certain embodiments, R 4 is hydrogen, Boc or Cbz. According to one embodiment, R 2 is Boc and M is sodium. According to one embodiment, R 4 is Boc and M is sodium. According to another embodiment, R 2 and R 4 are Boc and M is sodium.
  • the present invention provides a compound of formula K: wherein:
  • A is TFA, HC1, HBr, H3PO4, or H 2 SO 4 ; and n is 1, 2 or 3.
  • n is 3.
  • A is H2SO4.
  • aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as or/Ao-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include:
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a Ci-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a Ci-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2J/-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • Ci-s saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or
  • aryloxyalkyl refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 it electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 47/ quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 27/ pyrrol yl), NH (as in pyrrolidinyl), or + NR (as in N substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 37/ indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R* is C1-6 aliphatic
  • R* is optionally substituted with halogen, - R*, -(haloR*), -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or - NO 2
  • each R* is independently selected from C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently -R , -NR ⁇ , - C(NH)NR'?, or -N(R ⁇ )S(O) 2 R ⁇ ; wherein each R 1 ' is independently hydrogen, Ci-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R 1 ' is Ci-6 aliphatic, R' is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*),
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a warhead moiety, R 1 of a provided compound comprises one or more deuterium atoms.
  • an inhibitor is defined as a compound that binds to and /or inhibits CXCR4 with measurable affinity.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 pM, less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in CXCR4 activity between a sample comprising a compound of the present invention, or composition thereof, and CXCR4, and an equivalent sample comprising CXCR4, in the absence of said compound, or composition thereof.
  • n-heptane (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C. This step is repeated once as described below.
  • n-heptane (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B.
  • n-heptane (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min., discharge the lower aqueous phase to waste and charge the upper organic layer to vessel A.
  • Step 3B Preparation of amine P-1
  • Step 3C Preparation of compound 0-1
  • F-3a (1.1 eq, 0.64 wt) in 4 equal portions ensuring portions are spaced by 10 min. at 10°C.
  • TBAI tetrabutylammonium iodide
  • n-butanol (2.4 wt, 3.0 vol) to vessel B and adjust to 5°C.
  • Step 3E Preparation of Mavorixafor Drug Substance
  • the mavorixafor composition comprises 7000, 6000, 5000, 4500, 4450, 4000, 3500, 3000, 2500, 2000, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 ppm of toluene or less.
  • the mavorixafor composition comprises a detectable amount of toluene.
  • the mavorixafor composition comprises from a detectable amount of toluene to 1350 ppm of toluene. In some embodiments, the mavorixafor composition comprises from a detectable amount of toluene to 4450 ppm of toluene. In some embodiments, the mavorixafor composition comprises from 1750 ppm toluene to 4450 ppm of toluene. In some embodiments, the mavorixafor composition comprises from 1500 ppm toluene to 2500 ppm of toluene. In some embodiments, the mavorixafor composition comprises from a 1800 ppm toluene to 2200 ppm of toluene. In some embodiments, the mavorixafor composition comprises from a 1900 ppm toluene to 2100 ppm of toluene.
  • toluene is used as a crystallization solvent for isolation of X4P- 001.
  • a specification for residual toluene in X4P-001 freebase is such that the mavorixafor composition comprises no more than 4500 ppm.
  • the mavorixafor composition comprises no more than 4000 ppm, 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1750 ppm, 1700 ppm, 1650 ppm, 1600 ppm, 1550 ppm, 1500 ppm, 1450 ppm, 1400 ppm or 1350 ppm of toluene.
  • a permitted daily exposure (PDE) approach is used.
  • PDE permitted daily exposure
  • the term permitted daily exposure (PDE) is defined as a pharmaceutically acceptable intake of residual solvents in a drug. See, e.g., Guidance for Industry: Q3C Impurities: Residual Solvents published by the Department of Health and Human Services, Food and Drug Administration (FDA).
  • WO 2003/055876 describes the hydrobromide salt of mavorixafor and is hereby incorporated by reference.
  • US 7,723,525 which is hereby incorporated by reference, describes a number of attempts to prepare salt forms of mavorixafor and notes at column 2, lines 4-10, that many suffer from problems associated with hygroscopicity.
  • simple acid salts of mavorixafor such as hydrobromide and hydrochloride suffered from hygroscopicity.
  • US 7,723,525 One goal of the invention described in US 7,723,525 is to provide benzoate salts of mavorixafor having less hygroscopicity than the hydrobromide or hydrochloride salts, as well as increased stability (column 3, lines 55-65).
  • US 7,723,525 teaches that a group of benzoate salts such as 4-hydroxybenzoate, 4-aminobenzoate, 4-hydroxybenzenesulfonate, etc. had the desired properties (column 5, lines 3- 9).
  • the properties of other salts were unpredictable and many suffered from hygroscopicity as noted above. Formation of the mono-sulfate salt is described in Example 1 of US 7,723,525, but its hygroscopicity and stability are not described or suggested.
  • a trisulfate salt is mentioned, no such salt was prepared, nor were its properties determined or predicted.

Abstract

La présente invention concerne des procédés de synthèse d'inhibiteur de récepteur C-X-C de type 4 (CXCR4) de mavorixafor et de ses intermédiaires.
PCT/US2022/046094 2021-10-07 2022-10-07 Synthèse de mavorixafor et de ses intermédiaires WO2023059903A1 (fr)

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Citations (2)

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US7332605B2 (en) * 2004-03-15 2008-02-19 Anormed, Inc. Process for the synthesis of CXCR4 antagonist
US20200253953A1 (en) * 2018-08-31 2020-08-13 X4 Pharmaceuticals, Inc. Compositions of cxcr4 inhibitors and methods of preparation and use

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